Seminar 09-04-2014 Osteoporose en cni

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Seminar 09-04-2014 Osteoporose en cni

  1. 1.    Osteoporosebehandeling  bij  CKD         Joop  van  den  Bergh,  internist-­‐endocrinoloog   VieCuri  MC  Noord-­‐Limburg   Maastricht  UMC+   UHasselt,  België  
  2. 2. CBO  guideline  2011     Osteoporose  en  fractuurprevenIe   1.  PaIents  at  increased  risk  for  fracture     2.  EvaluaIon  of  skeletal  status  (DEXA/VFA)   3.  AnI-­‐osteoporosis  therapy:   •  BMD  T-­‐score  ≤  -­‐2.5   •  Vertebral  fracture(s)  
  3. 3. Studies  of  fracture  risk  associated  with  CKD   Kidney  InternaIonal  2008:  721–731   •  High  risk  of  fracture  because  of  low  bone  mineral  density   •  Resembles  or  is  higher  than  in  postmenopausal  osteoporosis    
  4. 4. However     •  The  mineral  and  bone  disorder  associated  with  CKD   (CKD–MBD)  is  more  complex  than  osteoporosis  and   the  same  treatments  might  not  be  appropriate.    
  5. 5.    Renal  osteodystrophy:  a  complex  interplay  of  geneIc,  growth   and  cellular  factors,  some  of  which  inhibit  bone  formaIon,   whereas  others  sImulate  bone  resorpIon    
  6. 6. Prevalence  of  low,  normal,  and  high  bone  turnover  in   black  and  white  CKD  paIents  on  maintenance  dialysis   JBMR  2011:  1368–1376   Review  of  630  bone  biopsies    
  7. 7. JBMR  2011:  1368–1376  
  8. 8. EvaluaIons  and  limitaIons  in  clinical  pracIce   •  Laboratory  parameters   •  Bone  turnover  markers   •  BMD  /  DEXA   •  HRpQCT   •  Bone  biopsy  
  9. 9. Laboratory  parameters  
  10. 10. Bone  turnover  markers:   levels  dependent  on  eGFR   Moorthi  et  al.  Kidney  InternaIonal  2013:886–894  
  11. 11. Studies  of  imaging  modaliIes  to  assess  fracture  status  in  paIents   with  CKD  that  report  test  diagnosIc  characterisIcs   Kidney  InternaIonal  2008:  721–731  
  12. 12. HR-­‐pQCT=  High  resoluIon  periferal  quanItaIve  computer  tomography  
  13. 13. HR-­‐pQCT  radius  (lei)  and  Ibia  (right)     B  healthy,  post-­‐  menopausal     C  predialysis  with  CKD  and  without  fracture   D  predialysis  with  CKD  with  prevalent  fracture   J  Am  Soc  Nephrol  21:  1371–1380,  2010  
  14. 14. BMD  and  HR-­‐pQCT  vs  fracture  predicIon   •  while  both  tests  were  able  to  discriminate  fracture  status,  the  addiIon  of   HR  pQCT  measures  to  BMD  by  DXA  did  not  improve  fracture   discriminaIon  ability   Osteoporos  Int  2012:2805–2813  
  15. 15. LimitaIons  in  clinical  pracIce   •  Overlap  in  laboratory  parameters   •  Bone  turnover  markers  influenced  by  eGFR   •  BMD  /  DEXA  provides  ‘only’  2D  density  parameters   •  PotenIal  role  of  HRpQCT  needs  to  be  further  studied   •  LimitaIons  for  bone  biopsies  (as  gold  standard)  in   clinical  pracIce   •  UlImately:  combinaIon  of  mulIple  imaging   techniques  and  biomarkers  that  are  specific  to  each   gender  and  race  in  CKD  to  predict  fracture  risk  
  16. 16. Considered  together   •  Fracture  risk  appears  to  be  higher  than  in  age-­‐  and   BMD-­‐matched  paIents  without  CKD   •  In  predialysis  CKD  without  substanIal  derangements   in  markers  of  mineral  metabolism  BMD  by  DXA  can   be  used  to  diagnose  osteoporosis   Jamal  et  al.  Curr  Rheumatol  Rep  (2012)  14:217–223  
  17. 17. CBO  guideline  2011     Osteoporose  en  fractuurprevenIe   1.  PaIents  at  increased  risk  for  fracture     2.  EvaluaIon  of  skeletal  status  (DEXA/VFA)   3.  AnI-­‐osteoporosis  therapy:   •  BMD  T-­‐score  ≤  -­‐2.5   •  Vertebral  fracture(s)  
  18. 18. Therapy  should  depend  on  the  underlying   pathophysiology    
  19. 19. Resorption Formation Teriparatide/ rec PTHBisphosphonates SERMs Denosumab % Change vs. baseline Bone  turnover  and  anI-­‐osteoporosis  medicaIon   Strontium Ranelate
  20. 20.  Nat.  Rev.  Nephrol.  Online  October  2013     Bone  Biopsies  with  tetracycline  double  labelling    
  21. 21.  J  Bone  Miner  Res  1997;12:191–199   Bone  Biopsies  with  tetracycline  double  labelling      Nat.  Rev.  Nephrol.  Online  October  2013    
  22. 22. Normal  bone  turnover   hop://courses.washington.edu/bonephys  
  23. 23. Adynamic  bone   hop://courses.washington.edu/bonephys  
  24. 24. OsteiIs  fibrosa  cysIca   hop://courses.washington.edu/bonephys  
  25. 25.  J  Bone  Miner  Res  1997;12:191–199   Bone  Biopsies  with  tetracycline  double  labelling      Nat.  Rev.  Nephrol.  Online  October  2013    
  26. 26. Fracture  outcomes  in  paIents  with  CKD–MBD   •  No  clinical  studies  to  assess  fracture  outcomes  in   paIents  with  CKD–MBD    
  27. 27. Risedronate  in  PaIents  With  Age-­‐Related   Reduced  Renal    FuncIon  :    A  Pooled    Analysis    of  Nine  Clinical  Trials   n=301  vs  271   J  Bone  Miner  Res  2005;20:2105–2115.   new  vertebral  fractures  
  28. 28. Bisphosphonate  use  in  paIents  with  CKD     •  Mainly  confined  to  those  with  early  stages  of  the  disease   •  Post  hoc  analyses  from  osteoporosis  clinical  trials:   –  paIents  with  mild  CKD  (but  normal  Ca,  AF  and  PTH)  have  a  similar   reducIon  in  fractures  to  that  observed  in  paIents  without  CKD   •  Histological  findings:  in  only  one  single-­‐centre,  observaIonal  study   –  in  all  13  paIents  with  CKD  stage  2–4  who  had  taken  bisphosphonates,   bone  biopsies  revealed  adynamic  bone  disease*.   •  The  KDIGO  commioee  could  not  idenIfy  any  clinical  trial  that  met   their  minimum  criteria  for  incorporaIon  into  their  consensus   guidelines:  inclusion  of  at  least  50  paIents  and  a  duraIon  of  at   least  6  months.   *Blood  Purif.  2010:293-­‐99  
  29. 29. jnephrol  2013;  26  (3):  450-­‐455   35%  administered  dose  cleared  by  hemodialysis  
  30. 30. Acute  Kidney  Injury  and  Bisphosphonate  Use   •  Preclinical  and  clinical  observaIons  reveal  that  all  BPs  can   potenIally  cause  acute  tubular  necrosis   •  Decline  in  GFR,  coupled  with  decreased  renal  blood  flow,   leads  to  reduced  drug  clearance  and  increased  concentraIon   of  drugs  in  the  renal  medulla   •  Mainly  aier  iv  dosing   •  In  cancer  paIents  (high  dose  and  co-­‐morbidity)   J  Oncology  PracIce  2013:101-­‐106  
  31. 31. Raloxifene  (SERM)   •  Raloxifene  is  excreted  via  hepaIc  metabolism,  and  serum   drug  concentraIons  are  about  1.4  Imes  higher  in  paIents   with  CKD  than  in  individuals  with  normal  renal  funcIon   •  Aier  1  year  raloxifene,  lumbar  spine  BMD  (trabecular  bone)   significantly  improved,  femoral  neck  BMD  (corIcal  bone)  did   not  change  significantly   •  Incidence  of  breast  cancer  is  lowered  by  70%   •  However,  raloxifene,  like  oestrogen,  increases  the  risk  of   thromboembolism   Kidney  InternaIonal  2003:2269–2274  
  32. 32. Denosumab   •  MAB  that  targets  the  osteoclast-­‐differenIaIon   cytokine  RANKL   –  Reducing  the  number  of  osteoclasts  and  bone  formaIon   rates     •  Is  not  excreted  by  the  kidney  
  33. 33. JBMR  2012:  1471   GFR  at  baseline  by  Cockcroi-­‐Gault  esImaIon:   •  normal  renal  funcIon  (GFR  >80  mL/min/1.73m2)   •  mild  CKD  (GFR  50–80  mL/min/1.73m2)   •  moderate  CKD  (GFR  30–49  mL/min/1.73m2)   •  severe  CKD  (GFR  <30  mL/min/1.73m2)   •  kidney  failure  requiring  hemodialysis  
  34. 34. Denosumab  in  paIents  with  CKD   •  None  had  stage  5  CKD   •  Fracture  risk  reducIon  and  changes  in  BMD  at  all  sites  were  in  favour  of  DMAb   •  The  test  for  treatment  by  subgroup  interacIon  was  not  staIsIcally  significant,   indicaIng  that  treatment  efficacy  did  not  differ  by  kidney  funcIon   JBMR  2011;1829  
  35. 35. •  Denosumab  has  not  been  available  long  enough  to  assess  its   long-­‐term  safety  in  paIents  with  CKD–MBD   •  Problems  related  to  suppression  of  bone  formaIon  are  likely   to  be  seen     Denosumab  in  paIents  with  CKD  
  36. 36. Hypocalcemia  aier  denosumab  in  severe  CKD   JBMR  2012:  1471   Calcium  and  vitamin  D  supplementaIon  was  not  iniIally  required  by   the  study  protocol,  but  was  added  during  the  trial   No  subject  who  received  adequate  calcium  and  vitamin  D   supplementaIon  became  hypocalcemic.  
  37. 37. Hypocalcemia   •  Increased  risk  of  post-­‐denosumab  and  iv  bisphophonate  hypocalcaemia  in   renal  impairment  may  result  from  sudden  inhibiIon  of  the  high  bone   turnover  that  occurs  in  secondary  hyperparathyroidism   •  Is  preventable  with  adequate  calcium  and  vitamin  D  supplementaIon   •  Measurement  of  serum  calcium  levels  at  8–14  days  post-­‐denosumab  may   be  useful  to  allow  Imely  detecIon  of  hypocalcaemia  and  insItuIon  of   early  treatment   Intern  Med  J.  2013  Nov;43(11):1243-­‐6  
  38. 38. Bone  turnover  and  BMD  aier  disconInuaIon  of  Denosumab     JCEM  2011:972–980  
  39. 39. Am  J  Nephrol  2012;36:238–244   HD  paIents  
  40. 40. HD  paIents   •  TeriparaIde  improved  BMD  with  adynamic  bone   disease,  although  no  staIsIcal  significance   •  PaIents  with  osteiIs  fibrosa,  ibandronate  did  not   improve  BMD  while  cinacalcet  reduced  BMD   Am  J  Nephrol  2012;36:238–244  
  41. 41. Cinacalcet  Effect  on  Risk  of  Fractures   Cunningham J, et al. Kidney Int. 2005;68:1793-1800. Week Event-FreeProbability 0 4 8 12 16 20 24 28 32 36 40 44 48 52 0.75 0.95 1.00 n = 487Placebo n = 697Cinacalcet Placebo Cinacalcet 0.90 0.85 0.80 470 445 419 404 367 314 136 132 120 117 112 109383 656 614 574 554 485 392 132 131 125 115 110 106513 P = 0.04 Pooled analysis of safety data from 4 similarly designed randomized, double-blind, placebo- controlled trials All patients received standard care with phosphate binders and vitamin D, if prescribed.
  42. 42. Risk  of  Hip  Fracture  May  be  Greater  Aier   Parathyroidectomy   1,0   1,7   0,0   0,2   0,4   0,6   0,8   1,0   1,2   1,4   1,6   1,8   2,0   No  Parathyroidectomy   Parathyroidectomy   Adjusted  Odds  Ra;o  for  Hip  Fracture   Jadoul  M,  et  al.  Kidney  Int.  2006;70:1358-­‐1366.   Dialysis  Outcomes  Prac;ce  PaBerns  Study  analysis  of  8,978  pa;ents  on          hemodialysis  with  and   without  a  history  of  parathyroidectomy  (2002-­‐2004)     P  =  0.02  
  43. 43. TeriparaIde   •  Recombinant  PTH  (1-­‐34)     –  Anabolic  effect     •  Small  observaIonal  studies  suggest  that  teriparaIde  might  be   beneficial  in  paIents  with  CKD–MBD     –  who  have  adynamic  bone  disease   –  who  have  undergone  parathyroidectomy    
  44. 44. Conclusions   •  PaIents  with  CKD   –  Have  a  high  risk  of  fracture  owing  to  their  low  BMD   –  ConvenIonal  medicaIons  for  osteoporosis  are  effecIve  at   reducing  fracture  rates  in  stage  3  CKD  and  normal  PTH,  Ca   and  phosphate  measurements   –  In  stage  4–5  CKD,  or  those  with  abnormal  PTH  and  mineral   values,  the  available  data  are  insufficient  to  determine   whether  these  commonly  used  medicaIons  are  effecIve   against  fractures  
  45. 45. Conclusions   •  Alendronate,  risedronate   •  Zoledronate  (iv)   •  Denosumab       •  Raloxifene     •  TeriparaIde   •  Cinacalcet   •  Not  recommended  CrCl  <  30  (some  data   for  risedronate  if  CrCl  15-­‐30)   •  Contra-­‐indicated  CrCl  <  35   •  Might  be  useful  in  hypercalcemia   •  Risk  of  hypocalcemia  CrCl  <  30,  risky  for   low  bone  turnover,     •  No  concerns,  in  HD  beneficial  effects;   the  best  current  choice  in  women  with   CKD  without  VTE  problems   •  Benefit  in  low  PTH  en  low  BMD   •  Possible  effect  on  fractures  in  SHPT  

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